U.S. patent number 7,494,995 [Application Number 11/432,787] was granted by the patent office on 2009-02-24 for phenylpyridylpiperazine compounds.
This patent grant is currently assigned to Les Laboratoires Servier. Invention is credited to Alexis Cordi, Patrice Desos, Pierre Lestage.
United States Patent |
7,494,995 |
Desos , et al. |
February 24, 2009 |
Phenylpyridylpiperazine compounds
Abstract
A compound selected from those of formula (I): ##STR00001##
wherein: R.sub.1 represents an NR.sub.3SO.sub.2R.sub.4 group
wherein: R.sub.3 represents a hydrogen atom or an alkyl group,
R.sub.4 represents an alkyl group, aryl group or NR.sub.5R.sub.6
group, R.sub.2 represents an alkyl, cycloalkyl or cycloalkylalkyl
group, and medicinal products containing the same which are useful
in treating conditions treatable by antagonists of type H.sub.3
central histamine receptors.
Inventors: |
Desos; Patrice (Bois-Colombes,
FR), Cordi; Alexis (Suresnes, FR), Lestage;
Pierre (La Celle-Saint-Cloud, FR) |
Assignee: |
Les Laboratoires Servier
(Courbevoie Cedex, FR)
|
Family
ID: |
35677562 |
Appl.
No.: |
11/432,787 |
Filed: |
May 11, 2006 |
Prior Publication Data
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Document
Identifier |
Publication Date |
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US 20060258671 A1 |
Nov 16, 2006 |
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Foreign Application Priority Data
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May 12, 2005 [FR] |
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05 04757 |
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Current U.S.
Class: |
514/235.8;
544/121; 544/364; 544/360; 514/253.13; 514/253.09; 514/253.01 |
Current CPC
Class: |
A61P
43/00 (20180101); A61P 25/24 (20180101); A61P
25/02 (20180101); A61P 25/04 (20180101); A61P
25/14 (20180101); A61P 25/28 (20180101); A61P
3/04 (20180101); A61P 29/00 (20180101); A61P
25/00 (20180101); A61P 25/08 (20180101); A61P
25/16 (20180101); C07D 213/74 (20130101) |
Current International
Class: |
A61K
31/4418 (20060101); C07D 213/72 (20060101); C07D
213/74 (20060101) |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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0361489 |
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Apr 1990 |
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EP |
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92/05156 |
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Apr 1992 |
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WO |
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99/21834 |
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May 1999 |
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WO |
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Leurs et al. TIPS, vol. 19, p. 177-183 (1998). cited by examiner
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other .
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by other .
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by other .
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other .
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by other .
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other .
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other .
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cited by other.
|
Primary Examiner: Bernhardt; Emily
Attorney, Agent or Firm: Hueschen and Sage
Claims
We claim:
1. A compound selected from those of formula (I): ##STR00005##
wherein: R.sup.1 represents an NR.sub.3SO.sub.2R.sub.4 group
wherein: R.sup.3 represents a hydrogen atom or a linear or branched
(C.sub.1-C.sub.6)alkyl group, R.sup.4 represents a linear or
branched (C.sub.1-C.sub.6)alkyl group, an aryl group or an
NR.sub.5R.sub.6 group wherein: R.sub.5 and R.sub.6, which may be
the same or different, each represent a hydrogen atom, a linear or
branched (C.sub.1-C.sub.6)alkyl group, a
(C.sub.3-C.sub.8)cycloalkyl group, or a
(C.sub.3-C.sub.8)cycloalkyl-(C.sub.1-C.sub.6)alkyl group in which
the alkyl moiety is linear or branched, or R.sub.5 and R.sub.6,
together with the nitrogen atom carrying them, form a 5- to
8-membered ring wherein one of the carbon atoms may be replaced by
a nitrogen, oxygen or sulphur atom or by an SO or SO.sub.2 group,
wherein the ring thereby defined is optionally bridged by a linear
or branched (C.sub.1-C.sub.6)alkylene group and is optionally
substituted by one or more identical or different groups selected
from halogen, linear or branched (C.sub.1-C.sub.6)alkyl, linear or
branched (C.sub.1-C.sub.6)alkoxy, linear or branched
(C.sub.1-C.sub.6) polyhaloalkyl, carboxy, hydroxy, cyano, nitro and
amino (optionally substituted by one or more linear or branched
(C.sub.1-C.sub.6)alkyl groups), R.sub.2 represents a linear or
branched (C.sub.1-C.sub.6)alkyl group, a
(C.sub.3-C.sub.8)cycloalkyl group or a
(C.sub.3-C.sub.8)cycloalkyl-(C.sub.1-C.sub.6)alkyl group wherein
the alkyl moiety may be linear or branched, it being understood
that: an aryl group means phenyl, naphthyl and biphenyl, wherein
such groups may be optionally substituted by one or more identical
or different groups selected from halogen, linear or branched
(C.sub.1-C.sub.6)alkyl, linear or branched (C.sub.1-C.sub.6)alkoxy,
linear or branched (C.sub.1-C.sub.6)poly-haloalkyl, carboxy,
hydroxy, cyano, nitro and amino (optionally substituted by one or
more linear or branched (C.sub.1-C.sub.6)alkyl groups), its
enantiomers and diastereoisomers, and addition salts thereof with a
pharmaceutically acceptable acid or base.
2. A compound of claim 1, wherein R.sub.4 represents an alkyl
group, its enantiomers and diastereoisomers, and addition salts
thereof with a phannaceutically acceptable acid or base.
3. A compound of claim 1, wherein R.sub.3 represents a hydrogen
atom, its enantiomers and diastereoisomers, and addition salts
thereof with a pharmaceutically acceptable acid or base.
4. A compound of claim 1, wherein R.sub.5 and R.sub.6, together
with the nitrogen atom carrying them, form a 5- to 8-membered ring
wherein one of the carbon atoms may be replaced by a nitrogen,
oxygen or sulphur atom or by an SO or SO.sub.2 group, its
enantiomers and diastereoisomers, and addition salts thereof with a
pharmaceutically acceptable acid or base.
5. A compound of claim 1, wherein R.sub.2 represents an isopropyl
group, its enantiomers and diastereoisomers, and addition salts
thereof with a pharmaceutically acceptable acid or base.
6. A compound of claim 1, wherein R.sub.2 represents a cyclopropyl
or cyclopentyl group, its enantiomers and diastereoisomers, and
addition salts thereof with a pharmaceutically acceptable acid or
base.
7. A compound of claim 1, which is
N-[4-[6-(4-cyclopentyl-1-piperazinyl)-3-pyridinyl]phenyl]methanesulphonam-
ide dihydrochioride, and addition salts thereof with a
pharmaceutically acceptable acid or base.
8. A process for the preparation of the compounds of formula (I) of
claim 1, wherein a compound of formula (II): ##STR00006## wherein R
and R', which may be the same or different, each represent a
hydrogen atom or a linear or branched (C.sub.1-C.sub.6)alkyl group
or together form a linear or branched (C.sub.1-C.sub.6)alkylene
chain, is condensed, in the presence of palladium(0), with a
compound of formula (III): ##STR00007## wherein Hal represents a
halogen atom, to yield the compound of formula (I), which compound
of formula (I) is purified, if necessary, according to a
conventional purification technique, is separated, where
appropriate, into its isomers according to a conventional
separation technique and is converted, if desired, into its
addition salts with a pharmaceutically acceptable acid or base.
9. A pharmaceutical composition comprising as active ingredient a
compound of claim 1 in combination with one or more inert,
non-toxic, pharmaceutically acceptable excipients or carriers.
10. A method for treating a living animal body, including a human,
afflicted with a condition selected from convulsive attacks,
attention deficit hyperactivity syndrome, obesity and narcoleptic
states, comprising the step of administering to the living animal
body, including a human, a compound of claim 1 which is effective
for alleviation of the condition.
11. A method for treating a living animal body, including a human,
afflicted with a condition selected from cognitive deficiencies
associated with Alzheimer's disease, comprising the step of
administering to the living animal body, including a human, a
compound of claim 1 which is effective for alleviation of the
condition.
Description
The present invention relates to new phenylpyridylpiperazine
compounds, to a process for their preparation and to pharmaceutical
compositions containing them.
The compounds of the present invention are especially valuable from
a pharmacological point of view because of their specific
interaction with type H.sub.3 central histamine receptors and can
be used in the treatment of neuropathologies associated with
cerebral ageing, mood disorders, eating behaviour and
sleep-wakefulness rhythm, and of attention deficit hyperactivity
syndrome.
Ageing of the population due to increased life expectancy at birth
has brought with it a large increase in the incidence of
age-related neuropathologies and especially of Alzheimer's disease.
The principal clinical manifestations of cerebral ageing and
especially of age-related neuropathologies are deficiencies in
memory and cognitive functions, which may lead to dementia.
Recent neuropharmacological studies have shown that, in the central
nervous system, histamine, via the central histaminergic systems,
has the role of a neurotransmitter or neuromodulator in
physiological or physiopathological situations (Annu. Rev.
Neurosci., 1986, 9, 209-254; Physiol. Rev., 1991, 71, 1-51). Thus,
it has been shown that histamine is involved in various
physiological and behavioural processes, such as thermoregulation,
neuro-endocrinal regulation, circadian rhythm, cataleptic states,
motility, aggressiveness, eating behaviour, learning and
memorisation, and synaptic plasticity (Hass et al., histaminergic
neurones: morphology and function, Boca Raton, Fla.: CRC Press,
1991, pp. 196-208; Prog. Neurobiology, 2001, 63, 637-672).
Of the 3 histamine receptor sub-types (H.sub.1, H.sub.2 and
H.sub.3), it was initially shown that the type H.sub.3 receptor is
a pre-synaptic autoreceptor which controls the release of histamine
(Nature, 1987, 327, 117-123). Its activation inhibits the release
and synthesis of histamine by a negative feedback mechanism
(Neuroscience, 1987, 23, 149-157). The existence of presynaptic
heteroreceptors capable of modulating the release of some
neuropeptides and of many neurotransmitters, such as noradrenaline,
serotonin, dopamine, GABA, acetylcholine and glutamate, was
demonstrated subsequently (TiPS, 1998, 19, 177-183). Studies
carried out in animals have shown that an increase in endogenous
extra-synaptic levels of histamine via blockage of type H.sub.3
receptors by H.sub.3 antagonists makes it possible to promote
states of vigilance, learning and memory processes, to regulate
food intake, and to combat convulsive attacks (Prog. Neurobiol.,
2000, 63, 637-672; Neurosci. Biobehav. Rev., 2000, 24, 107-113). As
a result, the potential therapeutic indications for H.sub.3
antagonists are the treatment of cognitive deficiencies associated
with cerebral ageing and with neurodegenerative diseases such as
Alzheimer's disease, Parkinson's disease, Pick's disease,
Korsakoff's disease and frontal or sub-cortical dementias of
vascular or other origin, and the treatment of mood disorders,
convulsive attacks, attention deficit hyperactivity syndrome,
obesity, pain and narcoleptic states.
The compounds of the present invention, in addition to having a
novel structure, have pharmacological properties which are entirely
surprising and valuable in this field.
More specifically, the present invention relates to compounds of
formula (I):
##STR00002## wherein R.sub.1 represents an NR.sub.3SO.sub.2R.sub.4
group wherein: R.sub.3 represents a hydrogen atom or a linear or
branched (C.sub.1-C.sub.6)alkyl group, R.sub.4 represents a linear
or branched (C.sub.1-C.sub.6)alkyl group, an aryl group or an
NR.sub.5R.sub.6 group wherein: R.sub.5 and R.sub.6, which may be
the same or different, each represent a hydrogen atom or a linear
or branched (C.sub.1-C.sub.6)alkyl group, a
(C.sub.3-C.sub.8)cycloalkyl group or a
(C.sub.3-C.sub.8)cycloalkyl-(C.sub.1-C.sub.6)alkyl group in which
the alkyl moiety is linear or branched, or R.sub.5 and R.sub.6,
together with the nitrogen atom carrying them, form a 5- to
8-membered ring wherein one of the carbon atoms may be replaced by
a nitrogen, oxygen or sulphur atom or by an SO or SO.sub.2 group,
the ring thereby defined optionally being bridged by a linear or
branched (C.sub.1-C.sub.6)alkyl group and/or optionally being
substituted by one or more identical or different groups selected
from halogen, linear or branched (C.sub.1-C.sub.6)alkyl, linear or
branched (C.sub.1-C.sub.6)alkoxy, linear or branched
(C.sub.1-C.sub.6)polyhaloalkyl, carboxy, hydroxy, cyano, nitro and
amino (optionally substituted by one or more linear or branched
(C.sub.1-C.sub.6)alkyl groups), R.sub.2 represents a linear or
branched (C.sub.1-C.sub.6)alkyl group, a
(C.sub.3-C.sub.8)cycloalkyl group or a
(C.sub.3-C.sub.8)cycloalkyl-(C.sub.1-C.sub.6)alkyl group wherein
the alkyl moiety may be linear or branched, it being understood
that:
an aryl group means the groups phenyl, naphthyl and biphenyl, those
groups optionally being substituted by one or more identical or
different groups selected from halogen, linear or branched
(C.sub.1-C.sub.6)alkyl, linear or branched (C.sub.1-C.sub.6)alkoxy,
linear or branched (C.sub.1-C.sub.6)poly-haloalkyl, carboxy,
hydroxy, cyano, nitro and amino (optionally substituted by one or
more linear or branched (C.sub.1-C.sub.6)alkyl groups),
to their enantiomers and diastereoisomers, and also to addition
salts thereof with a pharmaceutically acceptable acid or base.
Among the pharmaceutically acceptable acids there may be mentioned,
without implying any limitation, hydrochloric acid, hydrobromic
acid, sulphuric acid, phosphonic acid, acetic acid, trifluoroacetic
acid, lactic acid, pyruvic acid, malonic acid, succinic acid,
glutaric acid, fumaric acid, tartaric acid, maleic acid, citric
acid, ascorbic acid, methanesulphonic acid, camphoric acid etc.
Among the pharmaceutically acceptable bases there may be mentioned,
without implying any limitation, sodium hydroxide, potassium
hydroxide, triethylamine, tert-butylamine etc.
More especially, the invention relates to compounds of formula (I)
wherein R.sub.4 represents an alkyl group, for example a methyl
group.
Preference is given to the group R.sub.3 being a hydrogen atom.
Advantageously, the invention relates to compounds of formula (I)
wherein R.sub.5 and R.sub.6, together with the nitrogen atom
carrying them, form a 5- to 8-membered ring wherein one of the
carbon atoms may be replaced by a nitrogen, oxygen or sulphur atom
or by an SO or SO.sub.2 group, for example a morpholine group.
Preference is given to the R.sub.2 group being an isopropyl,
cyclopropyl or cyclopentyl group.
Even more especially, the invention relates to compounds of formula
(I) which are:
N-{4-[6-(4-isopropylpiperazin-1-yl)pyridin-3-yl]phenyl}benzenesulphonamid-
e dihydrochloride,
N-{4-[6-(4-cyclopentylpiperazin-1-yl)pyridin-3-yl]phenyl}benzenesulphonam-
ide dihydrochloride,
N-[4-[6-(4-cyclopentyl-1-piperazinyl)-3-pyridinyl]phenyl]methanesulphonam-
ide dihydrochloride,
N-{4-[6-(4-cyclopropylpiperazin-1-yl)pyridin-3-yl]phenyl}methanesulphonam-
ide dihydrochloride,
N-{4-[6-(4-isopropylpiperazin-1-yl)pyridin-3-yl]phenyl}morpholine-4-sulph-
onamide dihydrochloride,
N-{4-[6-(4-isopropylpiperazin-1-yl)pyridin-3-yl]phenyl}methanesulphonamid-
e dihydrochloride,
N-{4-[6-(4-isopropylpiperazin-1-yl)pyridin-3-yl]phenyl}propane-2-sulphona-
mide dihydrochloride,
N-{4-[6-(4-cyclopentylpiperazin-1-yl)pyridin-3-yl]phenyl}-4-fluorobenzene-
sulphonamide dihydrochloride,
N-{4-[6-(4-cyclopentylpiperazin-1-yl)pyridin-3-yl]phenyl}-3-fluorobenzene-
sulphonamide dihydrochloride,
N-{4-[6-(4-cyclopentylpiperazin-1-yl)pyridin-3-yl]phenyl}-2-fluorobenzene-
sulphonamide dihydrochloride.
The invention relates also to a process for the preparation of
compounds of formula (I), which process is characterised in that
there is used, as starting material, the compound of formula
(II):
##STR00003## wherein R.sub.1 is as defined for formula (I), and R
and R', which may be the same or different, each represent a
hydrogen atom or a linear or branched (C.sub.1-C.sub.6)alkyl group
or together form a linear or branched (C.sub.1-C.sub.6)alkylene
chain, which is condensed, in the presence of palladium(0), with a
compound of formula (III):
##STR00004## wherein R.sub.2 is as defined for formula (I) and Hal
represents a halogen atom, to yield the compound of formula (I),
which compound of formula (I) is purified, if necessary, according
to a conventional purification technique, is separated, where
appropriate, into its isomers according to a conventional
separation technique and is converted, if desired, into its
addition salts with a pharmaceutically acceptable acid or base.
The compounds of formulae (II) and (III) as defined hereinbefore
are either commercially available or obtained by conventional
reactions of organic chemistry.
By virtue of their pharmacological properties as H.sub.3 histamine
receptor ligands, the compounds of the present invention are useful
in the treatment of cognitive deficiencies associated with cerebral
ageing and with neurodegenerative diseases, such as Alzheimer's
disease, Parkinson's disease, Pick's disease, Korsakoff's disease
and frontal or sub-cortical dementias of vascular or other origin,
and also in the treatment of mood disorders, convulsive attacks,
attention deficit hyperactivity syndrome, obesity, pain and
narcoleptic states.
The present invention relates also to pharmaceutical compositions
comprising as active ingredient at least one compound of formula
(I), an isomer thereof or an addition salt thereof with a
pharmaceutically acceptable acid or base, alone or in combination
with one or more inert, non-toxic, pharmaceutically acceptable
excipients or carriers.
Among the pharmaceutical compositions according to the invention,
there may be mentioned more especially those that are suitable for
oral, parenteral (intravenous, intramuscular or subcutaneous), per-
or trans-cutaneous, intravaginal, rectal, nasal, perlingual,
buccal, ocular or respiratory administration.
The pharmaceutical compositions according to the invention for
parenteral injections especially include aqueous and non-aqueous
sterile solutions, dispersions, suspensions or emulsions as well as
sterile powders for the reconstitution of injectable solutions or
dispersions.
The pharmaceutical compositions according to the invention for
solid oral administration especially include tablets or dragees,
sublingual tablets, sachets, capsules and granules, and for liquid
oral, nasal, buccal or ocular administration especially include
emulsions, solutions, suspensions, drops, syrups and aerosols.
The pharmaceutical compositions for rectal or vaginal
administration are preferably suppositories, and those for per- or
trans-cutaneous administration especially include powders,
aerosols, creams, ointments, gels and patches.
The above-mentioned pharmaceutical compositions illustrate the
invention but do not limit it in any way.
Among the inert, non-toxic, pharmaceutically acceptable excipients
or carriers there may be mentioned, without implying any
limitation, diluents, solvents, preservatives, wetting agents,
emulsifiers, dispersants, binders, swelling agents, disintegrants,
retardants, lubricants, absorbency agents, suspension agents,
colourants, flavourings etc.
The useful dosage varies according to the age and weight of the
patient, the route of administration, the pharmaceutical
composition used, the nature and severity of the disorder, and
whether any associated treatments are being taken. The dosage
ranges from 10 mg to 1 g per day in one or more
administrations.
The following Preparations and Examples illustrate the invention
but do not limit it in any way. The starting materials used are
known products or are prepared according to known procedures. The
structures of the compounds described in the Examples were
determined in accordance with the usual spectrophotometric
techniques (infrared, NMR, mass spectrometry etc.).
Preparation 1
1-(5-Bromopyridin-2-yl)-4-isopropylpiperazine
A solution containing 12.1 g of 2,5-dibromopyridine (51.1 mmol),
8.8 ml of 1-isopropylpiperazine (61.5 mmol) and 9.2 ml of DBU (61.5
mmol) is stirred overnight at 100.degree. C. The reaction mixture
is returned to ambient temperature and the solution is diluted with
water and extracted with ethyl acetate. The organic phases are
collected, washed with brine, dried (MgSO.sub.4) and evaporated
under reduced pressure. The residue is chromatographed on an
SiO.sub.2 column, eluting with a mixture of CH.sub.2Cl.sub.2/MeOH
98/2 and then 96/4, to yield the title product.
Melting Point: 76-78.degree. C.
Elemental Microanalysis:
TABLE-US-00001 C H N Br %, theory 50.72 6.38 14.79 28.12 %,
experiment 50.96 6.47 14.53 28.33
Preparation 2
1-(5-Bromopyridin-2-yl)-4-cyclopentylpiperazine
Identical procedure to that of Preparation 1, but the
1-isopropylpiperazine is replaced by 1-cyclopentylpiperazine.
Melting Point: 127-128.degree. C.
Preparation 3
1-(5-Bromopyridin-2-yl)-4-cyclopropylpiperazine
Identical procedure to that of Preparation 1, but the
1-isopropylpiperazine is replaced by 1-cyclopropylpiperazine.
Melting Point: 110-115.degree. C.
EXAMPLE 1
N-{4-[6-(4-Isopropylpiperazin-1-yl)pyridin-3-yl]phenyl}benzene-sulphonamid-
e dihydrochloride
Step A: N-(4-Iodophenyl)benzenesulphonamide
To a solution of 2.0 g of 4-iodoaniline (9.13 mmol) in 40 ml of
acetonitrile there are added 1.48 ml of pyridine (18.26 mmol) and
then, dropwise, a solution of 1.28 ml of benzenesulphonyl chloride
(10 mmol) in 20 ml of acetonitrile. The reaction mixture is stirred
overnight at ambient temperature and the acetonitrile is evaporated
off under reduced pressure. The residue is taken up in 1N HCl and
extracted with ethyl acetate. The organic phase is washed with
brine, dried (MgSO.sub.4) and evaporated under reduced pressure.
The oily residue obtained is triturated in isopropyl ether until
the title product crystallises.
Melting Point: 141-143.degree. C.
Step B:
N-[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]benzene-s-
ulphonamide
500 mg of the compound obtained in Step A (1.39 mmol), 389 mg of
bis(pinacolato)diborane (1.53 mmol), 410 mg of potassium acetate
(4.18 mmol) and 5 ml of dimethylformamide are introduced into a 25
ml two-necked flask. The reaction mixture is degassed by bubbling
through a current of nitrogen for 30 minutes, and then 16 mg of
palladium acetate (0.07 mmol) are added. The reaction mixture is
stirred under a gentle current of nitrogen for 7 hours at
85.degree. C. After cooling to ambient temperature, the reaction
mixture is diluted with water and extracted with ethyl acetate. The
organic phases are combined, washed with brine, dried and
evaporated under reduced pressure. The residue from evaporation is
triturated in heptane to yield, after filtration, the title product
in the form of a white solid.
Melting Point: 157-160.degree. C.
Step C:
N-{4-[6-(4-Isopropylpiperazin-1-yl)pyridin-3-yl]phenyl}benzene-sul-
phonamide dihydrochloride
226 mg of the compound obtained in Preparation 1 (0.79 mmol), 300
mg of the compound obtained in Step B (0.83 mmol), 3 ml of dioxane
and 3 ml of 0.4M aqueous Na.sub.2CO.sub.3 solution are introduced
into a 25 ml two-necked flask. The reaction mixture is degassed by
bubbling nitrogen through for 30 minutes. Pd(0)
tetrakistriphenylphosphine (45 mg, 0.04 mmol) is introduced and the
reaction mixture is stirred at 90.degree. C. under a gentle current
of nitrogen for 3 hours. After cooling to ambient temperature, the
reaction mixture is diluted with water and extracted with ethyl
acetate. The extracted phases are combined, washed with brine,
dried (MgSO.sub.4) and evaporated under reduced pressure. The
residue obtained is chromatographed on SiO.sub.2
(CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH 96/4/0.4) to yield the title
product in the form of the base. The base is dissolved in ethereal
HCl and then the solution is concentrated and filtered to yield the
title product in the form of the hydrochloride.
Melting Point: 160-163.degree. C.
Elemental Microanalysis:
TABLE-US-00002 C H N S Cl %, theory 56.58 5.93 11.00 6.29 13.92 %,
experiment 55.36 6.3 10.62 6.32 13.67
EXAMPLE 2
N-{4-[6(4-Cyclopentylpiperazin-1-yl)pyridin-3-yl]phenyl}benzene-sulphonami-
de dihydrochloride
The product obtained in Step B of Example 1 is reacted with the
compound obtained in Preparation 2, under the conditions described
in Step C of Example 1.
Melting Point: 162-167.degree. C.
Elemental Microanalysis:
TABLE-US-00003 C H N S Cl %, theory 58.31 6.02 10.46 5.99 13.24 %,
experiment 58.71 6.05 10.53 6.03 12.66
EXAMPLE 3
N-[4-[6-(4-Cyclopentyl-1-piperazinyl)-3-pyridinyl]phenyl]methane-sulphonam-
ide dihydrochloride
Step A: N-(4-Iodophenyl)methanesulphonamide
Identical procedure to Step A of Example 1, but the
benzenesulphonyl chloride is replaced by methanesulphonic
anhydride.
Melting Point: 118-120.degree. C.
Elemental Microanalysis:
TABLE-US-00004 C H N S I %, theory 28.30 2.71 4.71 10.79 42.71 %,
experiment 28.67 2.83 4.70 11.22 43.44
Step B:
N-[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methane-s-
ulphonamide
Identical procedure to Step B of Example 1, but starting from the
product obtained in Step A above.
Melting point: 180-182.degree. C.
Step C:
N-[4-[6-(4-Cyclopentyl-1-piperazinyl)-3-pyridinyl]phenyl]methane-s-
ulphonamide dihydrochloride
Identical procedure to Step C of Example 1, starting from the
product obtained in Step B and replacing the compound obtained in
Preparation 1 by the compound obtained in Preparation 2.
Melting Point: 227-229.degree. C.
Elemental Microanalysis:
TABLE-US-00005 C H N S Cl %, theory 53.27 6.39 11.83 6.77 14.98 %,
experiment 53.22 6.41 11.43 6.85 14.89
EXAMPLE 4
N-{4-[6-(4-Cyclopropylpiperazin-1-yl)pyridin-3-yl]phenyl}methane-sulphonam-
ide dihydrochloride
The product obtained in Step B of Example 3 is reacted with the
compound obtained in Preparation 3, under the conditions described
in Step C of Example 1.
Melting Point: 197.degree. C.
Elemental Microanalysis:
TABLE-US-00006 C H N S Cl %, theory 51.24 5.88 12.58 7.20 15.92 %,
experiment 51.70 5.78 12.21 6.81 15.93
EXAMPLE 5
N-{4-[6-(4-Isopropylpiperazin-1-yl)pyridin-3-yl]phenyl}morpholine-4-sulpho-
namide dihydrochloride
Step A: N-(4-Iodophenyl)morpholine-4-sulphonamide
To a solution of 10 g of 4-iodoaniline (45.6 mmol) in 200 ml of
acetonitrile there are added 6.41 ml of Et.sub.3N (45.6 mmol) and
8.47 g of morpholine-4-sulphonyl chloride (45.6 mmol). The reaction
mixture is stirred for 16 hours at ambient temperature. The
acetonitrile is evaporated off in vacuo, and the residue is taken
up in 1N HCl and extracted with CH.sub.2Cl.sub.2. The organic
phases are combined, washed with brine, dried (MgSO.sub.4) and
treated with animal charcoal to yield the title product.
Melting Point: 91.degree. C.
Step B:
N-[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]morpholin-
e-4-sulphonamide
Identical procedure to Step B of Example 1, starting from the
product obtained in Step A.
Melting Point: 158-161.degree. C.
Step C:
N-{4-[6-(4-Isopropylpiperazin-1-yl)pyridin-3-yl]phenyl}morpholine-
-4-sulphonamide dihydrochloride
Identical procedure to Step C of Example 1, starting from the
product obtained in Step B.
Melting Point: 194-198.degree. C.
Elemental Microanalysis:
TABLE-US-00007 C H N S Cl %, theory 50.96 6.41 13.51 6.18 13.67 %,
experiment 50.90 6.79 13.23 6.09 13.46
EXAMPLE 6
N-{4-[6-(4-Isopropylpiperazin-1-yl)pyridin-3-yl]phenyl}methane-sulphonamid-
e dihydrochloride
The product of Step B of Example 3 is reacted with the compound
obtained in Preparation 1, under the conditions described in Step C
of Example 1.
Melting Point: 191.degree. C.
Elemental Microanalysis:
TABLE-US-00008 C H N S Cl %, theory 50.19 6.25 12.32 7.05 17.15 %,
experiment 50.14 6.10 11.49 6.58 17.25
EXAMPLE 7
N-{4-[6(4-Isopropylpiperazin-1-yl)pyridin-3-yl]phenyl}propane-2-sulphonami-
de dihydrochloride
Step A: N-(4-Iodophenyl)propane-2-sulphonamide
Identical procedure to Step A of Example 5 replacing
morpholine-4-sulphonyl chloride with propane-2-sulphonyl
chloride.
Melting Point: 96.degree. C.
Elemental Microanalysis:
TABLE-US-00009 C H N S I %, theory 33.24 3.72 4.31 9.86 39.03 %,
experiment 33.21 3.38 4.17 9.74 38.37
Step B:
N-[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propane--
2-sulphonamide
Identical procedure to Step B of Example 1, starting from the
product obtained in Step A.
Melting Point: 192.degree. C.
Elemental Microanalysis:
TABLE-US-00010 C H N S %, theory 55.40 7.44 4.31 9.86 %, experiment
55.46 7.33 4.54 10.11
Step C:
N-{4-[6-(4-Isopropylpiperazin-1-yl)pyridin-3-yl]phenyl}propane-2--
sulphonamide dihydrochloride
Identical procedure to Step C of Example 1, starting from the
product obtained in Step B.
Melting Point: 165.degree. C.
Elemental Microanalysis:
TABLE-US-00011 C H N S Cl %, theory 53.05 6.78 11.78 6.74 14.91 %,
experiment 53.05 7.07 11.58 6.47 14.62
EXAMPLE 8
N-{4-[6-(4-Cyclopentylpiperazin-1-yl)pyridin-3-yl]phenyl}4-fluorobenzenesu-
lphonamide dihydrochloride
Step A:
{4-[6-(4-Cyclopentylpiperazin-1-yl)pyridin-3-yl]phenyl}amine
Identical procedure to Step C of Example 1, using
[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]amine.
Melting Point: 160-162.degree. C.
Step B:
N-{4-[6-(4-Cyclopentylpiperazin-1-yl)pyridin-3-yl]phenyl}-4-fluor-
obenzenesulphonamide dihydrochloride
A suspension containing 200 mg (0.620 mmol) of the product obtained
in Step A and 302 mg (1.55 mmol) of 4-fluorophenylsulphonic acid
chloride in 2 ml of pyridine is stirred for 3 hours at 80.degree.
C. After cooling to ambient temperature, the reaction mixture is
precipitated by adding water. The precipitate is collected by
filtration, dissolved in a mixture of CH.sub.2Cl.sub.2/MeOH,
absorbed onto about 1 g of silica and chromatographed on a silica
column, eluting with a mixture of CH.sub.2Cl.sub.2/MeOH/NH.sub.3
98/2/0.2. The dihydrochloride is formed by taking up the base in
ethanol and adding ethereal HCl.
Melting Point: 256-262.degree. C.
Elemental Microanalysis:
TABLE-US-00012 C H N S Cl %, theory 56.42 5.64 10.12 5.79 12.81 %,
experiment 56.03 5.73 9.77 5.45 12.74
EXAMPLE 9
N-{4-[6-(4-Cyclopentylpiperazin-1-yl)pyridin-3-yl]phenyl}-3-fluorobenzene--
sulphonamide dihydrochloride
Identical procedure to Example 8, but using 3-fluorophenylsulphonic
acid chloride in Step B.
Melting Point: 167-170.degree. C.
Elemental Microanalysis:
TABLE-US-00013 C H N S Cl %, theory 56.42 5.64 10.12 5.79 12.81 %,
experiment 56.72 5.60 9.96 5.67 12.86
EXAMPLE 10
N-{4-[6-(4-Cyclopentylpiperazin-1-yl)pyridin-3-yl]phenyl}-2-fluoro-benzene-
sulphonamide dihydrochloride
Identical procedure to Example 8, but using 2-fluorophenylsulphonic
acid chloride in Step B.
Melting Point: 248-253.degree. C.
Elemental Microanalysis:
TABLE-US-00014 C H N S Cl %, theory 56.42 5.64 10.12 5.79 12.81 %,
experiment 56.46 5.63 9.87 5.47 12.80
Pharmacological Study of Compounds of the Invention
Example A
Cerebral Levels of N.sup..tau.-Methylhistamine in the NMRI
Mouse
The purpose of this study, which was carried out in accordance with
the method of Taylor et al. (Biochem. Pharm., 1992, 44, 1261-1267),
is to evaluate the ex vivo activity of the compounds of the present
invention as antagonists of type H.sub.3 central histamine
receptors. That activity is revealed by measuring, after treatment
intraperitoneally with the test compounds, the central levels of
N.sup..tau.-methylhistamine, which is a main metabolite of
histamine. An increase in the cerebral concentrations of
N.sup..tau.-methylhistamine indicates an increase in the turn-over
of histamine by blockage of the type H.sub.3 central histamine
receptors.
NMRI mice (18-20 g) are treated intraperitoneally or orally with
compounds of the present invention or with their carrier (20
ml/kg). One hour after the pharmacological treatment, the animals
are sacrificed, and their brains are removed, frozen in liquid
nitrogen, weighed and homogenised in 0.1N HClO.sub.4 at 4.degree.
C. The homogenised products are centrifuged (15 000 g, 17 min,
4.degree. C.). The supernatants are recovered and divided into
aliquots. The aliquots are frozen in liquid nitrogen and stored at
-80.degree. C. until analysis.
Determination of the cerebral levels of N.sup..tau.-methylhistamine
is carried out by radio-immunological assay (RIA) using an assay
kit. The tissue levels of N.sup..tau.-methylhistamine are expressed
in .mu.g/g of fresh brain. The comparison of the cerebral levels of
N.sup..tau.-methylhistamine between animals treated with the
carrier (controls) and animals treated with compounds of the
present invention is carried out by single-factor variance analysis
followed, if necessary, by a complementary analysis (Dunnett's
test).
The results show that, at doses of from 1 to 10 mg/kg PO, the
compounds of the present invention are capable of increasing
endogenous cerebral concentrations of N.sup..tau.-methylhistamine
by 100%.
By way of example, the compounds of Examples 4 and 7, administered
at doses of 10 mg/kg and 3 mg/kg PO, respectively, allow an
increase in the endogenous cerebral concentrations of
N.sup..tau.-methylhistamine of 162% and 138%, respectively, to be
obtained.
These results demonstrate that the compounds of the present
invention are powerful antagonists of type H.sub.3 central
histamine receptors.
Example B
Electroencephalographic Recordings on Freely Moving Rats
Adult male Wistar rats were chronically implanted with electrodes
placed over the frontal and parietal cortex. Cortical
electroencephalogram (EEG) was recorded from rats placed inside
cages in a sound attenuating-room. Compounds and vehicle were
administered in a random order at 10:00 AM on the same days with a
minimum of 3 days between each administration, allowing each rat to
serve as its own control. Absolute power of slow wave delta band
activity (1-4 Hz), that predominates during slow wave sleep and
disappears during wakefulness and rapid eyes movement sleep, was
averaged over successive periods of 30 min. Over 30 min, low and
high values of slow wave delta power are signs of arousal and
sleep, respectively.
Results indicate that compounds of the present invention increase
arousal (decrease of delta band activity) for doses ranging between
0.3 to 3 mg/kg IP.
Example C
Pharmaceutical Composition
TABLE-US-00015 Preparation formula for 1000 tablets each containing
a 100 g dose of 100 mg of N-[4-[6-(4-cyclopentyl-1-piperazinyl)-
3-pyridinyl]phenyl]methanesulphonamide dihydrochloride (Example 3)
Hydroxypropylcellulose 2 g Wheat starch 10 g Lactose 100 g
Magnesium stearate 3 g Talc 3 g
* * * * *